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Nat Commun. 2019 Mar 26;10(1):1373. doi: 10.1038/s41467-019-09068-2.

Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.

Author information

1
Departments of Medicine, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA.
2
UTSW Simmons Cancer Center, Dallas, TX, 75230, USA.
3
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA.
4
Departments of Biochemistry, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA.
5
Vanderbilt Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, 37232-6307, TN, USA.
6
Departments of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA.
7
Robert H Lurie Comprehensive Cancer Center, Chicago, 60611, IL, USA.
8
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 02114, MA, USA.
9
Baylor University Medical Center, Texas Oncology, , US Oncology, Dallas, 75246, TX, USA.
10
Guardant Health, Redwood City, 94063, CA, USA.
11
Novartis Institutes for Biomedical Research, Cambridge, 02139, MA, USA.
12
Novartis Pharmaceuticals Corporation, East Hanover, 07936, NJ, USA.
13
Departments of Medicine, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA. carlos.arteaga@utsouthwestern.edu.
14
UTSW Simmons Cancer Center, Dallas, TX, 75230, USA. carlos.arteaga@utsouthwestern.edu.
15
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 37232-6307, TN, USA. carlos.arteaga@utsouthwestern.edu.

Abstract

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.

PMID:
30914635
PMCID:
PMC6435685
DOI:
10.1038/s41467-019-09068-2
[Indexed for MEDLINE]
Free PMC Article

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